combined t cell depleted haploidentical peripheral blood stem cell and unrelated umbilical cord blood transplantation in patients with hematologic malignancies using a total lymphoid irradiation based preparative regimen

Conditions: Hematological Malignancies

Summary: in this study, participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (hct), who do not have a suitable human leukocyte antigen (hla)-matched related/sibling donor (msd), matched unrelated donor (murd) or killer-immunoglobulin receptors (kir) ligand mismatched haploidentical donor identified, will receive a combined t cell depleted (tcd) haploidentical peripheral blood stem cell (pbsc) and unrelated umbilical cord blood transplantation (ucbt) using a total lymphoid irradiation (tli) based preparative regimen. primary objective: * to estimate the incidence of donor derived neutrophil engraftment by day +42 post-transplant for participants with high-risk hematologic malignancies undergoing a total lymphoid irradiation (tli)-based hematopoietic cell transplantation (hct) using a t cell depleted (tci) haploidentical donor peripheral blood stem cell (pbsc) donor combined with an unrelated umbilical cord blood (ucb) donor. secondary objectives: * estimate the incidence of malignant relapse, event-free survival (efs), and overall survival (os) at one-year post-transplantation. * estimate the incidence and severity of acute and chronic graft versus host disease (gvhd) in the first 100 days after transplantation. * estimate the incidence of secondary graft failure transplant related mortality (trm) and transplant related morbidity in the first 100 days after hct.

prior to stem cell infusion, participants will receive a preparative regimen of total lymphoid irradiation (tli), fludarabine, cyclophosphamide, melphalan, and thiotepa to prepare their bone marrow. thereafter, they will receive a hematopoietic cell graft from a haploidentical donor and an unrelated umbilical cord blood donor. post-transplantation immunosuppressive treatment will include tacrolimus and mycophenolate mofetil.

Eligibility criteria:
inclusion criteria-transplant recipient: * age less than or equal to 21 years old. * does not have a suitable matched related/sibling donor (msd) or volunteer matched unrelated donor (mud) available in the necessary time for stem cell donation. * has a suitable partially human leukocyte antigen (hla)-matched (≥ 3 of 6) family member donor. * has a partially hla-matched single umbilical cord blood (ucb) unit (≥ 4 of 6) with adequate cell dose. ucb units must fulfill eligibility as outlined in 21 cfr 1271 and agency guidance. * high-risk hematologic malignancy. * high risk acute lymphocytic leukemia (all) in complete remission-1 (cr)1. \[examples include, but not limited to t(9;22), hypodiploid,, m2 or greater marrow at the end of induction, infants with mixed lineage leukemia (mll) fusion or t(4;11)\]. * all in high risk cr2. \[examples include but not limited to t(9;22), bone marrow (bm) relapse \<36 mo cr1, t-all, very early (\< 6mo cr1) isolated central nervous system (cns) relapse.\] * all in cr3 or subsequent. * acute myeloid leukemia (aml) in high risk cr1. \[examples include but not limited to preceding mds, 5q-, -5, -7, fab m6, fab m7 not t(1;22), minimal residual disease (mrd) ≥ 5% on day 22 (aml08), m3 marrow after induction 1, m2 marrow after two cycles of induction, flt3-itd.\] * aml in cr2 or subsequent. * therapy related aml, with prior malignancy in cr \> 12mo * myelodysplastic syndrome (mds), primary or secondary * natural killer (nk) cell, biphenotypic, or undifferentiated leukemia in cr1 or subsequent. * chronic myeloid leukemia (cml) in accelerated phase, or in chronic phase with persistent molecular positivity or intolerance to tyrosine kinase inhibitor. * hodgkin lymphoma in cr2 or subsequent after failure of prior autologous hematopoietic cell transplantation (hct), or unable to mobilize stem cells for autologous hct. * non-hodgkin lymphoma in cr2 or subsequent. * juvenile myelomonocytic leukemia (jmml). * refractory hematologic malignancies \[all, aml, chronic myeloid leukemia (cml) in blast crisis, hodgkin or non-hodgkin lymphoma\] due to chemoresistant relapse or primary induction failure. * all patients with evidence of cns leukemia must be treated and be in cns cr to be eligible for study. * patient must fulfill pre-transplant evaluation: * cardiac function: left ventricular ejection fraction (lvef) ≥ 40% or shortening fraction (sf) ≥ 25%. * creatinine clearance (crcl) or glomerular filtration rate (gfr) ≥ 50 ml/min/1.73m2. * forced vital capacity (fvc) ≥ 50% of predicted value or pulse oximetry (pox) ≥ 92% on room air. * karnofsky or lansky performance score ≥ 50. * bilirubin ≤ 3 times the upper limit of normal for age. * alanine aminotransferase (alt) ≤ 5x the upper limit of normal for age. * aspartate aminotransferase (ast) ≤ 5x the upper limit of normal for age. exclusion criteria - transplant recipient: * patient has a suitable msd, volunteer matched unrelated donor (murd), or killer-immunoglobulin receptors (kir) mismatched haploidentical donor available in the necessary time for stem cell donation. * patient has any other active malignancy other than the one for which hct is indicated. * patient is pregnant as confirmed by positive serum or urine pregnancy test within 14 days prior to enrollment. * patient is breast feeding. * patient has down syndrome. * patient has a current uncontrolled bacterial, fungal, or viral infection per the judgment of the principal investigator. inclusion criteria - haploidentical donor * at least single haplotype matched (≥ 3 of 6) family member * at least 18 years of age. * human immunodeficiency virus (hiv) negative. * not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female). * not breast feeding. * regarding eligibility, is identified as either: * completed the process of donor eligibility determination as outlined in 21 cfr 1271 and agency guidance; or * does not meet 21 cfr 1271 eligibility requirements, but has a declaration of urgent medical need completed by the principal investigator or physician sub-investigator per 21 cfr 1271.

Keywords: cord blood haploidentical reduced intensity regimen